Basic, translational and clinical studies attest to the pivotal role of plasminogen in numerous physiological and pathophysiological responses. In many of these processes, the involvement of plasminogen arises from its influence on inflammatory cell recruitment, which in turn depends upon its interaction with plasminogen receptors (Plg-Rs) on the responding cells. Plg-Rs are expressed ubiquitously, are present at high density on most cells and most frequently interact with the lysine binding sites of plasminogen. Examples of responses involving inflammatory cell recruitment in which plasminogen and Plg-Rs have been implicated include peritonitis, sepsis, lung injury, angiogenesis, restenosis, atherogenesis, aneurysm and the response to biomaterial implants. Plg-Rs are heterogeneous and include ones with transmembrane domains (tailed Plg-Rs) and without transmembrane domains (tailless Plg-Rs). On macrophages, the tailless Plg-Rs, histone H2B, annexin2, p11 and a-enolase, account for most of the plasminogen binding capacity of the cells. Leukocyte integrin aMb2 represents a tailed Plg-R, which, when activated, can assemble plasminogen, the urokinase plasminogen activator and its receptor into a functional complex. A panel of blocking antibodies to these five major Plg-Rs has been developed, have been shown to be specific for their target Plg-R, and can be administered in vivo as Fab fragments to inhibit inflammatory responses. These reagents will allow for the first objective dissection of the contribution of individual Plg-Rs in biologically relevant inflammatory responses.
In Aim 1, we will deploy these antibody reagents in various inflammatory response models, sepsis, angiogenesis and airway hypersensitivity, to test the hypothesis that Plg-Rs are utilized in cellular recruitment in a stimulus and tissue specific manner. The tailless Plg-Rs reach the cell surface through a common mechanism involving calcium mobilization via L-type calcium channels, but the mechanism by which they tether to the cell surface is unresolved.
In aim 2, a series of questions will be addressed which will determine if the tailless Plg-Rs anchor to the macrophage surface through a common mechanism and to identify this mechanism. Differences in localization of these Plg-Rs on migrating macrophages will also be assessed. The unexpected findings that plasminogen controls macrophage uptake of oxidized lipoproteins to form foam cells and additionally regulates expression of proatherogenic genes in these cells will be investigated in Aim 3. The Plg-Rs that mediates foam cell formation and the pathway involved in this regulatory role of plasminogen will be identified. Taken together, these studies will define how plasminogen and its receptors function in biologically important responses.
Inflammation is a critical element in numerous diseases, and binding of plasminogen to its receptors plays a fundamental role in recruitment of cells to sites of inflammation. By identifying the plasminogen receptors involved in specific inflammatory responses, we will define new therapeutic targets for ameliorating many diseases.
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